HCV and HIV infections often occur concurrently in high-risk populations such as injection drug users, due to the overlapping modes of transmission. Moreover, HCV infection has emerged as a significant cause of morbidity and mortality in HCV-HIV coinfected individuals. One possible mechanism by which this occurs is through impairment of host immune function. Consistent with impaired host immune function is the finding that immunization induced immunity is reduced in the setting of HCV-HIV infection compared to HCV or HIV monoinfection, suggesting that both HCV and HIV infection affect the developing host immune response. As hypothesized in Project 2, one mechanism by which immune impairment may occur is through gut bacterial translocation, potentially leading to increased T cell activation and turnover. One possible means for this T cell activation may be the result of gut bacterial product mediated dendritic cell (DC) activation, in turn leading to T cell activation. In the setting of HCV infection gut bacterial translocation may be enhanced, due to impaired gut host surveillance immunity, or altered portal hemodynamics in the setting of HCV induced liver cirrhosis. Another mechanism for HCV-HIV infected host immune impairment may be directly due to defects in DC numbers or function beyond those present in the setting of HIV infection, resulting in diminished host immune response. Dendritic cells are primary innate immune effectors able to enhance NK cell mediated immunity, and key to formation of adaptive immunity through priming naive T cells. Human DC can be divided into 2 main subsets (MDC and PDC; myeloid and plasmacytoid DC). Dendritic cell subset numbers and function are impaired in different ways comparing HCV and HIV infection. By understanding the proteomic profile associated with cellular immune modulation caused by HCV infection, we intend to gain a better understanding of HCV-HIV disease pathogenesis. In the current project we will explore the hypothesis that in the setting of HIV infection HCV infection affects MDC and PDC numbers and function. These effects are hypothesized to in turn result in enhanced immune activation reflected by serum and T cell proteomic profiles by A) determining, in the setting of HIV infection, the effect of HCV infection on DC number, DC response to TLR ligand, and serum proteomic profile of immune activation; and B) determining the effect of HCV infection on HIV infected host T cell activation.